SUMMARY Cigarette smoking increases the risk of multiple cancers, accounting for more than 30% of all cancer deaths and 80% of deaths from lung cancer. Disparities exist in smoking-related disease burden by socioeconomic and racial/ethnic status, and the cancer survival gap between blacks and whites has failed to close in 2 decades. Improved strategies are needed for underserved groups. Personalizing standard care with biological data to 1) enhance accuracy of lung cancer risk or 2) measure speed of nicotine metabolism to inform pharmacotherapy choice is a promising yet understudied approach in low income minority smokers. Such biologically-informed personalized treatment could benefit smokers by increasing motivation to quit, improving the accuracy of smoking-related health risk perceptions, or via other mechanisms. Smokers undergoing the gene-based lung cancer risk assessment, Respiragene (developed by Dr. Young, consultant) were more likely to undergo lung cancer screening, use nicotine replacement therapy (NRT) and quit smoking. Another promising tool for personalized intervention is the nicotine metabolite ratio (NMR), a biomarker reflecting the ratio of two nicotine metabolites (3'hydroxycotinine/cotinine) that closely approximates CYP2A6 gene activity. The NMR is considered the emerging biomarker of choice to measure nicotine metabolism, which can be dichotomized as ?fast/normal? vs ?slow.? Trial data from Dr. Tyndale (consultant) show that NMR informs choice of smoking cessation pharmacotherapy such that ?fast/normal? metabolizers are twice as likely to quit smoking on varenicline compared to ?slow? metabolizers. Neither of these promising interventions have been studied in vulnerable smokers receiving health care in the community. Taken together, these preliminary data set a compelling stage for personalized treatment of smoking in the Southern Community Cohort Study (SCCS). Our overarching aim is to leverage the SCCS and the Outreach Core Community Advisory Board (CAB) to guide the development of two personalized care (PC) interventions for smoking cessation: PC-Respiragene and PC-NMR. PC-Respiragene and PC-NMR are rooted in the PRIME Model of behavior change which reflects a multi-faceted view of motivation for tobacco cessation. Both will be tailored to attitudes and beliefs of low socioeconomic status (defined as majority of the population < 100% federal poverty level) smokers in the southeastern US, where tobacco use prevalence is very high. Aim 1 will survey SCCS smokers residing in Tennessee and Mississippi to assess attitudes and beliefs on smoking-related health risk perceptions, personalized smoking treatment, and willingness to join a smoking cessation trial of PC (n=1647). Aim 2 will leverage CAB input to develop PC-Respiragene and PC-NMR for use among diverse, low SES community smokers in the SCCS. Aim 3 will conduct a 3-arm RCT (N=75) SCCS smokers to pilot PC-Respiragene and PC-NMR interventions for feasibility and determine preliminary estimates of biochemically-validated smoking cessation and lung cancer screening at 6 months vs. guideline based care (GBC). Completion of these aims will lay groundwork for a large RCT of personalized smoking cessation in the SCCS.